This invention was made with government support under R01-HL40411, HL43344, and R04870, awarded by The National Institutes of Health. The government has certain rights in the invention.
1. Field of the Invention
This invention relates to the use of low molecular weight S-nitrosothiols, such as S-nitroso-N-acetylcysteine, S-nitroso-glutathione, S-nitroso-homocysteine, S-nitroso-cysteine, S-nitroso-penicillamine and S-nitroso-captopril, to relax non-vascular smooth muscle. Types of smooth muscle include airway, gastrointestinal, bladder uterine, and corpus cavernosum. The invention also relates to the use of S-nitrosothiols for the treatment or prevention of disorders which involve non-vascular smooth muscle, such as respiratory disorders, gastrointestinal disorders, urological dysfunction, impotence, uterine dysfunction or premature labor. The invention also relates to the use of S-nitrosothiols to ameliorate smooth muscle contraction or spasm and thus, facilitate diagnostic or therapeutic procedures, such as bronchoscopy, endoscopy, laparoscopy, and cystoscopy. S-nitrosothiols may also be used to increase hemoglobin-oxygen binding, and thus enhance oxygen transport to bodily tissues.
2. Brief Description of the Background Art
The endothelium secretes a vascular relaxing factor, known as endothelium-derived relaxing factor (EDRF), which has been identified as nitric oxide (NO), or a closely related derivative thereof. (Palmer et al., Nature 327: 524-526 (1987); Ignarro et al., Proc. Natl. Acad. Sci. USA 84: 9265-9269 (1987)). Under physiologic conditions, however, NO is exceedingly unstable, reacting essentially instantaneously with oxygen, superoxide anion, and redox metals (Lancaster et al., Proc. Natl. Acad. Sci. USA 87: 1223-1227 (1990); Ignarro et al., Circ. Res. 65: 1-21 (1989); and Gryglewski et al., Nature 320: 454-456 (1986)). This fact has lead to the supposition that, in order to exert its effect on vascular smooth muscle, NO must be stabilized in vivo in a form that preserves its biological activity.
S-nitrosothiols (RS-NO) are adducts that form readily under physiologic conditions from the reaction of NO with reduced low molecular weight thiols (Oae et al., Org. Prep. Proc. Int. 15(3): 165-198 (1983)). These compounds have half-lives that are significantly greater than that of NO and, like EDRF, possess vasorelaxant activity that is mediated through activation of guanylate cyclase (Kowaluk et al., J. Pharmacol. Exp. Ther. 256: 1256-1264 (1990); Loscalzo et al., J. Pharmacol. Exp. Ther. 249(3): 726-729 (1989); and Ignarro et al., J. Pharmacol. Exp. Ther. 218(3): 739-749 (1981)).
The relaxant effect of S-nitrosothiols on blood vessels, and the mechanism by which this effect is exerted, is reasonably well understood in the art. However, the role of NO, or involvement of the guanylate cyclase pathway in non-vascular smooth muscle is not as clearly understood.
Pulmonary immune responses result in the liberation of cytokines and inflammatory mediators which contribute to the narrowing of airway smooth muscle. As part of this process, pulmonary endothelial cells, macrophages and polymorphonuclear leukocytes are believed to induce nitric oxide synthetase, thus serving as a source of NO. The consequences of NO production in the lung are not known. However, the potential beneficial effects of NO through bronchodilation may be counterbalanced by generation of toxic nitrogen oxides that form readily under the high ambient concentration of oxygen and other reactive oxygen species.
Likewise, introduction of NO into the lungs also results in significant adverse effects, which occur as a direct result of the particular chemical reactivity of the uncharged NO radical (NO.). These adverse effects create impediments to NO therapy which generally involves administration of NO.. For example, the reaction between NO., and O.sub.2 or reactive O.sub.2 species which are present in high concentrations in the lung, generates highly toxic products, such as NO.sub.2 and peroxynitrite. These reactions also result in the rapid inactivation of NO, thus eliminating any beneficial pharmacological effect. (Furchgott R. F. et al., I. Endothelium-Derived Relaxing Factors and Nitric Oxide; eds. Rubanyi G. M., pp. 8-21 (1990); Gryglewski, R. J. et al., Nature 320: 454-456 (1986)). Furthermore, NO. reacts with the redox metal site on hemoglobin to form methemoglobin, which inhibits oxygen-hemoglobin binding, thereby significantly reducing the oxygen-carrying capacity of the blood.
Non-vascular smooth muscle is present in numerous organ systems throughout the body, and has a vital role in the physiological function of these systems. For example, airway smooth muscle plays a critical role in constriction and dilation of bronchi. In the gastrointestinal tract, the sphincter of Oddi, a smooth muscle connection between the bile duct and duodenum, provides tonic contraction which serves to prevent reflux of duodenal contents into the pancreatic and bile ducts, and promotes filling of the gall bladder. In addition, esophageal (sphincters and body), intestinal and colonic motility is regulated by smooth muscle. Smooth muscle of the bladder body, bladder base, and proximal urethra plays an important role in urological function, and erectile function is mediated by relaxation of corpus cavernosal smooth muscle.
In summary, the relaxation kinetics of non-vascular smooth muscle are very important in numerous physiological systems. Moreover, a variety of significant clinical disorders occur, which involve contraction, spasm, or failure to achieve the necessary relaxation of smooth muscle. Examples of such disorders include airway obstruction (i.e., asthma, bronchitis and emphysema), bladder dysfunction, gastrointestinal muscle spasm (i.e., irritable bowel syndrome, achalasia, dumping disorders), and impotence. Thus, a clinical need exists for pharmacological agents which can treat or prevent such disorders by inducing relaxation of the affected smooth muscle.